臺灣博碩士論文加值系統

牛血清白蛋白(BSA)具有生物相容性、生物可降解性、無毒性、低成本和良好的水溶性等特性，再加上其具有多種官能基，如羥基、羧基和硫醇基等等，可用於交聯和藥物的偶聯，因此BSA被認為是一種有潛力的藥物載體。而在乳腺癌細胞系中，能發現一種過度表達的果糖轉運蛋白－GLUT5，此受體被證明能夠應用於乳腺癌的標靶藥物治療上。透過D-glucose的還原胺化反應，能對BSA進行修飾，在其表面上形成果糖胺的結構，藉此使BSA能被GLUT5識別。
阿黴素(doxorubicin, DOXO)是治療乳腺癌常見的化療藥物。在本研究中，首先製備了具有果糖胺結構的糖基化牛血清白蛋白(F-BSA)，然後使用6-maleimido-hexanoic acid將阿黴素改質，並透過maleimide-thiol reaction使阿黴素與F-BSA的硫醇基結合，形成穀胱甘肽敏感的maleimide-thiol group。然而，有證據顯示BSA分子太小而無法受惠於腫瘤組織的enhanced permeability and retention (EPR) effect，因此我們透過desolvation method將阿黴素/糖基化牛血清白蛋白偶合物(F-BSA-DOXO)進一步製成粒徑較大的奈米粒子(NPs)。
本研究所製備出的奈米粒子為球狀，平均粒徑為60.74 ± 18.38 nm，ζ-potential為-42.20 ± 5.75 mV，而loading capacity (LC%)則為3.57%。製備出的F-BSA-DOXO NPs是以傅立葉轉換紅外線光譜(FTIR)來分析化學結構；接著使用體外藥物釋放來研究F-BSA-DOXO NPs的藥物釋放行為；最後對MCF-7以及CHO-K1細胞進行MTT試驗以評估F-BSA-DOXO NPs的抗癌活性以及選擇性，並透過共軛焦雷射掃描顯微鏡來觀察細胞對藥物的攝取。本研究的結果表明，F-BSA-DOXO NPs為乳腺癌標靶藥物治療的潛力候選藥物。

Bovine serum albumin (BSA) is considered a potential drug carrier due to its nontoxicity, biocompatibility, biodegradability in vivo, low cost, and good solubility in water. Also, BSA has various functional groups, such as hydroxyl groups, carboxylic acid groups, and thiol/sulfhydryl groups, which can be applied to cross-linkage and drug coupling. A type of fructose transporter, GLUT5, is overexpressed in breast cancer lines and has been shown to be a promising receptor for targeted drug delivery in breast cancer therapy. Upon glycation by the reductive amination of D-glucose, the fructosamine structure was formed on the glycated serum albumin (e.g., bovine serum albumin; BSA) which can be recognized by GLUT5.
Doxorubicin (DOXO) is known as a commonly used chemotherapy drug to treat breast cancer. In this study, the fructosamine structure-carrying glycated bovine serum albumin (F-BSA) was first prepared, followed by coupling with DOXO using 6-maleimidohexanoic acid to form the glutathione-sensitive maleimide-thiol group. Evidence indicates that the drug-encapsulated glycated proteins are inclined to be rapidly removed from tumors; therefore, efforts have been devoted to synthesizing the drug-encapsulated glycated protein nanoparticles via desolvation method to augment the enhanced permeability and retention (EPR) effect.
The nanoparticles were spherical with a mean size of 60.74 ± 18.38 nm (mean ± SD) and a ζ-potential of -42.20 ± 5.75 mV. The loading capacity was found to be 3.57%. Fructosamine assay was applied to the determination of the amount of fructosamine structures. The formation of synthesized F-BSA-DOXO nanoparticles (NPs) conjugates were verified by Fourier-transform infrared spectroscopy (FTIR). Next, the drug release behavior of the synthesized F-BSA-DOXO conjugates was further evaluated using the in vitro dialysis release method. The anticancer activity and selectivity of F-BSA-DOXO NPs were evaluated by performing MTT assay on MCF-7 cell lines and CHO-K1 cell lines. Finally, the cellular uptake was measure by confocal laser scanning microscopy (CLSM). The outcome from this study suggests that F-BSA-DOXO NPs serve as potential candidates for targeted drug delivery carriers used in breast cancer therapy.

口試委員審定書 I
誌謝 II
大綱 III
Abstract IV
目錄 VI
圖目錄 IX
表目錄 XII
第一章 文獻回顧 1
1.1乳腺癌(breast cancer) 1
1.1.1乳腺癌簡介 1
1.1.2 Glucose transporter type 5 (GLUT 5)簡介 6
1.1.3 Enhanced permeability and retention (EPR) effect簡介 7
1.2阿黴素簡介 8
1.3牛血清白蛋白簡介 12
1.3.1 Desolvation method簡介 16
1.3.2 Maleimide-thiol reaction簡介 17
1.4還原胺化反應(reductive amination)簡介 19
1.5實驗檢測原理介紹 20
1.5.1果糖胺檢測方法(Fructosamine assay) 20
1.5.2 MTT試驗(MTT assay) 21
第二章 研究動機 22
第三章 實驗儀器、藥品、細胞與步驟 24
3.1實驗儀器 24
3.2實驗藥品與細胞 26
3.3實驗方法和步驟 31
3.3.1主要溶液配製 31
3.3.2糖基化牛血清白蛋白(F-BSA)製備 34
3.3.3糖基化牛血清白蛋白奈米粒子(F-BSA NPs)製備 35
3.3.4阿黴素改質步驟(M-DOXO製備) 36
3.3.5阿黴素/糖基化牛血清白蛋白偶合物(F-BSA-DOXO)製備 37
3.3.5.1製備步驟 37
3.3.5.2 Loading capacity以及encapsulation efficiency估算 38
3.3.6阿黴素/糖基化牛血清白蛋白偶合物奈米粒子製備 39
3.3.6.1 F-BSA-DOXO NPs製備 39
3.3.6.2 F-BSA-DOXO NPs*製備 40
3.3.7果糖胺檢測方法(Fructosamine assay) 41
3.3.8穿透式電子顯微鏡(TEM) 42
3.3.9傅立葉轉換紅外線光譜儀(FTIR) 42
3.3.10動態光散射粒徑分析儀及界面電位分析儀 42
3.3.11體外藥物釋放實驗 43
3.3.11.1 DTT存在與否對體外藥物釋放的影響 43
3.3.11.2環境pH值以及藥物偶合方法對體外藥物釋放的影響 43
3.3.12細胞培養條件 44
3.3.12.1 MCF-7培養方式 44
3.3.12.2 CHO-K1培養方式 44
3.3.13 MTT試驗 45
第四章 實驗結果與討論 46
4.1阿黴素/糖基化牛血清白蛋白偶合物奈米粒子特性 46
4.1.1粒徑分布以及zeta potential 46
4.1.2 Loading capacity以及encapsulation efficiency 49
4.2穿透式電子顯微鏡觀察結果 50
4.2.1 pH值與交聯劑添加與否對BSA NPs粒徑以及型態的影響 50
4.2.2離子強度對F-BSA-DOXO NPs粒徑以及型態的影響 53
4.3果糖胺檢測方法實驗結果 56
4.4傅立葉轉換紅外線光譜分析 60
4.5體外藥物釋放實驗 63
4.5.1 DTT存在與否對體外藥物釋放的影響 63
4.5.2環境pH值以及藥物偶合方法對體外藥物釋放的影響 66
4.6 MTT試驗 69
第五章 結論 75
參考文獻 77
附錄 91

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